Our ultimate goal is to determine how developmental exposure to toxicants that utilize nuclear receptor systems (e.g., TCDD, peroxisome proliferators, retinoids, environmental estrogens, etc.) disrupts gene expression and produces resultant cellular defects. This proposal focuses on the mechanism by which one such toxicant (diethylstilbestrol or DES) alters expression of the c-fos protooncogene in the reproductive tract of developing rodents. Using this established in vivo model for human exposure to environmental estrogens, including the in utero exposure of humans to DES in the l96Os, we have obtained preliminary data that DES causes a persistent induction of c-fos expression in the reproductive tracts of both male and female animals. These observations led to our HYPOTHESIS that developmental exposure to estrogens causes epigenetic changes in the structure of the c-fos protooncogene to alter its expression and thereby disrupt the normal function of target cells. Specific aims to test this hypothesis are: * Determine the molecular mechanism by which DES increases basal fos expression. * Define the hormonal regulation of fos expression after developmental exposure to DES. * Identify the uterine and seminal vesicle cell types in which fos expression is altered, define specific pathological changes in these cells, and analyze their growth properties. * Assess the relationship between elevated fos expression and the frequency and severity of subsequent tissue lesions. The health relatedness of this project is two-fold. (l) The conceptual goal is to develop a unifying molecular model for receptor-mediated developmental defects caused by a number of environmental toxicants. (2) The specific experimental findings may increase our understanding of the effects of in utero exposure of humans to DES in the l960s and l970s, and of chronic low level exposure to environmental estrogens that may now be occurring throughout development.